tbuckley/cabot-search huggingface dataset:
Lung cancer metabolomics: A pooled analysis in the cancer prevention studies.
Authors: Ziyin Tang, Donghai Liang, Emily L Deubler, Jeremy A Sarnat, Sabrina S. Chow, Ryan Diver, Ying Wang
Journal: Journal of Clinical Oncology (2023)

10508 Background: Lung cancer is a heterogeneous disease, often diagnosed at advanced stages, with low overall survival rate. To better understand the lung cancer etiology and discover screening and early detection biomarkers, we performed a nested case-control study to examine the metabolic perturbation related to lung cancer. Methods: This study included 741 case-control pairs (mean age = 67 years) from the ongoing Cancer Prevention Study (CPS) cohorts. Participants completed a comprehensive exposure and health questionnaire at enrollment. Pre-diagnosis blood samples were collected between 1998-2001 in CPS-II and 2006-2013 in CPS-3. Cases and controls were 1:1 matched on date of birth, blood draw date, gender, and race/ethnicity. All eligible controls were cancer-free at the time of case diagnosis. Odds ratios (ORs) per standard deviation and 95% confidence intervals (CIs) were estimated using conditional logistic regression, controlling for potential confounders including body mass index, fruit and vegetable consumption, smoking status, and hormone use. We further performed stratified analyses by smoking status (never/former/current) and follow-up time (i.e., within 3 years/ beyond 3 years between blood draw and diagnosis). Statistical significance was determined as false discovery rate (FDR) &lt; 0.2. Results: Sphingomyelin (d18:0/22:0), a bioactive sphingolipid of cell membranes, was associated with lung cancer risk (OR:1.32, 95% CI: [1.15, 1.53], FDR = 0.12). When stratified by follow-up time, participants diagnosed within 3 years of blood draw had a 59% higher risk of lung cancer per standard deviation increase in sphingomyelin (d18:0/22:0) (OR:1.58, 95% CI: 1.16, 2.15, p = 0.004) and 25% higher risk for those diagnosed beyond 3 years (OR:1.27, 95% CI: 1.08, 1.50, p = 0.005). Metabolites associated with lung cancer at raw p-value &lt; 0.05 indicated the perturbation mostly in lipid, amino acid, and xenobiotics metabolism. We observed variants in perturbed metabolic pathways between never-smoker lung cancer cases and current-smoker lung cancer cases. Conclusions: This is the largest prospective study examining lung cancer risk and metabolic response using an untargeted metabolomics platform. These findings provide preliminary support for sphingomyelin (d18:0/22:0) as a potential screening and early detection biomarker for lung cancer. Results also highlight that lipid metabolism including sphingolipid and bile acid metabolism may play an important role in lung cancer etiology.
Prospective evaluation of cell-free DNA fragmentation profiles for lung cancer detection.
Authors: Kwok-Kin Wong, Peter J. Mazzone, Jun-Chieh Tsay, Harvey I. Pass, Anil Vachani, Jeffrey C. Thompson, Allison Ryan, Jacob Carey, Debbie Jakubowski, Tony Wu, Yuhua Zong, Carter Portwood, Keith Lumbard, Joseph Catallini, Kavita Arjungi, Ashley Birch, Alessandro Leal, Peter Brian Bach, Robert B. Scharpf, Victor E. Velculescu
Journal: Journal of Clinical Oncology (2023)

e20521 Background: Annual lung cancer screening can save lives, but fewer than 10% of eligible persons participate each year. More widespread screening is hindered by cost, inaccessibility, and uncertainty over individual-level benefit vs risk. Screening rates could be raised by a simple, inexpensive initial blood test, if it were sensitive for cancer detection. The DELFI (DNA evaluation of fragments for early interception) technology uses low-coverage, whole-genome sequencing and machine learning to identify patterns of cell-free DNA (cfDNA) fragmentation associated with cancer. Here we report preliminary cfDNA analysis results from DELFI-L101 (NCT04825834), a prospective, observational, multistate case-control study to train and test DELFI classifiers for lung cancer detection. Methods: Enrollees were ≥50 years old with current or previous smoking histories of ≥20 pack-years and recent or planned chest CT imaging. Medical history was recorded at enrollment, and blood samples were collected for DELFI analysis. Repeated 10-fold cross-validation was used to develop a classifier for lung cancer detection. A split study approach is planned for independent validation of the classifier. Results: At this time, 242 individuals with lung cancer and 652 without cancer have enrolled. Most participants were ≥65 years old, and the proportions of men and women were similar. Lung cancer risk factors were present among both cases and controls. Like the lung cancer screening population, approximately half of lung cancer cases were stage I. Median DELFI scores were higher among individuals with lung cancer than no cancer, overall and across groups stratified by age or body mass index (BMI). Cross-validated area under the receiver operator characteristic curve was 0.81 for lung cancer detection. Clinically meaningful sensitivity to detect lung cancer was attained across all disease stages, with sensitivity increasing stepwise with stage. Conclusions: We developed a classifier based on cfDNA fragmentome patterns analyzed using DELFI that could differentiate between lung cancer cases and controls with cross-validated performance across age groups, BMI categories, and cancer stages. A blood-based DELFI fragmentome test could serve as a low-cost, high-performance blood test with potential to improve lung cancer screening efficiency. Clinical trial information: NCT04825834 .
Association between duration of immunotherapy and overall survival in advanced non–small-cell lung cancer.
Authors: Lova Sun, Benjamin Aaron Bleiberg, Wei-Ting Hwang, Melina Elpi Marmarelis, Corey J. Langer, Aditi Puri Singh, Roger B. Cohen, Ronac Mamtani, Charu Aggarwal
Journal: Journal of Clinical Oncology (2023)

9101 Background: For patients (pts) with advanced non-small cell lung cancer (NSCLC) treated with front line immunotherapy-based treatment, the optimal duration of immune checkpoint inhibitor (ICI) treatment is unknown. We aimed to assess practice patterns surrounding ICI treatment discontinuation at two years, and to evaluate association of duration of therapy with overall survival by comparing pts who received fixed duration ICI therapy for 2 years vs those who continued therapy beyond two years. Methods: This study used the nationwide Flatiron Health electronic health record (EHR)-derived de-identified database, and included adult pts diagnosed with advanced NSCLC from 2016-2020, who received frontline immunotherapy-based treatment. Pts who were still on treatment without progression at 2 years were classified as “fixed duration” (treatment discontinuation at 2 years, between 700-760 days) vs “indefinite duration” (continued treatment beyond two years, &gt; 760 days). Overall survival from 760 days was analyzed using Kaplan-Meier methodology. Multivariable Cox regression adjusted for patient and cancer-specific factors was used to compare survival between fixed and indefinite-duration groups. Results: Our analytic cohort consisted of 113 pts in the fixed duration group and 593 in the indefinite duration group; median age was 69, 49% were female, and 71% were White. Pts in the fixed duration group were more likely to have a history of smoking and be treated at an academic center. There was no significant difference in overall survival between pts in the fixed duration and indefinite duration groups, either on univariable (HR 1.26, 95% CI 0.77-2.08) or multivariable Cox regression (HR 1.33, 95% CI 0.78-2.25). Conclusions: In a real world cohort of advanced NSCLC pts treated with front line ICI, only about 1 in 5 stopped treatment at two years rather than continuing treatment beyond two years. The lack of significant overall survival advantage for the indefinite duration cohort on adjusted analysis provides reassurance to pts and providers who wish to stop therapy at 2 years.
A real-world analysis of nonmetastatic non–small-cell lung cancer in Italy.
Authors: Immacolata Esposito, Giulia Ronconi, Letizia Dondi, Silvia Calabria, Carlo Piccinni, Antonella Pedrini, Leonardo Dondi, Irene Dell'anno, Alice Addesi, Nello Martini
Journal: Journal of Clinical Oncology (2023)

e20566 Background: The majority of all lung cancer cases are represented by non-small cell lung cancer (NSCLC), for which the standard of care is surgical resection. Chemotherapy, radiotherapy and immunotherapy are the most important perioperative systemic treatments. This study aimed to identify newly NSCLC diagnosed, non-metastatic (i.e., stages I-III) and resected patients, and characterize them from the perspective of the Italian National Health Service (INHS). Methods: From the Fondazione ReS (Ricerca e Salute) database (~5 million inhabitants/year), in 2017 (accrual period), patients with a new in-hospital diagnosis of NSCLC (i.e., excluding those diagnosed back up to 2013), at stage I-III (i.e., excluding those with distant metastases at the first diagnosis and/or within 60 following days), and resected (i.e., with ≥1 in-hospital surgery within 6 months from the first diagnosis), were identified. The cohort was characterized by age, sex and comorbidities. The dispensation of neoadjuvant therapy (≥1 radio and/or chemotherapy session) between the first diagnosis and surgery was analyzed. Within 2 years after surgery, overall survival-OS and progression free survival-PFS (Kaplan Meier analyses), and healthcare integrated costs charged to the INHS (pharmaceuticals, hospitalizations, specialist/outpatient services) were described. Results: In 2017, of 2440 (incidence 52.1 x100,000) newly NSCLC diagnosed patients, 1605 were defined with stage I-III. Of these, 467 (29.1%) underwent surgery. They were mainly males (74.3%) and on average aged 69±10. Arterial hypertension (64.7%), chronic lung diseases (46.7%) and dyslipidaemia (36.0%) were the most frequent comorbidities. Lung lobectomy (highest mean length of in-hospital stay: 11 days) was the most common surgery (296/467; 63.4%). Before surgery, 48/467 patients (10.3%) received neoadjuvant therapy. During the 2 nd year after surgery, 418/467 patients (89.5%) were analysable. At 2 years after surgery, OS was 81.6% and increased with age, while PFS was 59.8%. On average: within 1 year, the INHS spent € 20,942 per capita (hospitalizations – including first hospitalization - accounted for 56.3%, and pharmaceuticals for 35% of the total cost); within the 2 nd year, the INHS expenditure was € 9,851 per capita (pharmaceuticals weighed 65.8% of the overall cost, and hospitalizations 19.8%). Conclusions: Italian administrative healthcare data can identify and describe newly NSCLC diagnosed patients with stage I-III and resected, quantify their burden on the INHS and show a substantial survival benefit.
Association of weight loss with risk of myelodysplastic syndromes (MDS) in adults with obesity: Insights from the SPLENDID cohort.
Authors: Rahul Mishra, Rickesha Wilson, Chao Tu, Alex Milinovich, Hetty E Carraway, Jame Abraham, Ali Aminian, Abhay Singh
Journal: Journal of Clinical Oncology (2023)

e18865 Background: MDS arises from pre-existing somatic mutations or clonal hematopoiesis (CH). A normal body mass index (BMI) is strongly associated with a lower prevalence of CH. We hypothesized that intentional weight loss (IWL) might be associated with lower incidence of MDS and studied this in the context of bariatric surgery (BSx) among adults with obesity. Methods: In the SPLENDID (Surgical Procedures and Long-term Effectiveness in Neoplastic Disease Incidence and Death) matched cohort study, adults with BMI ≥35Kg/m 2 who had BSx (ages 18-80) during 2004-2017 were included. Each patient (pt) who underwent BSx was matched with propensity score by the nearest-neighbor method to five pts who did not undergo BSx for their obesity, resulting in a total of 30318 pts. MDS diagnosis was made using contemporary WHO criteria and myeloid sequencing mutation data were analyzed. Multivariable cox regression analysis estimated time to MDS as the primary endpoint. Results: 5053 adults with obesity had BSx while 25265 adults underwent nonsurgical (NS) care. Median age and BMI were 46 years (y) and 45kg/m 2 . The majority were females (77%); and had white (73%) race. Follow-up was over 17y period with median (IQR) of 6.1 (3.8-8.9)y for the entire cohort. BSx-group had 19.2% greater WL at 10-y [mean between-group difference: 24.8 (95% CI, 24.6-25.1) kg]. One patient (male) in the BSx-group vs twenty-four patients (twelve females) in the NS-group developed MDS (incidence rate: 0.03 vs 0.14, per 1000 person-years). A fully adjusted hazard ratio was 0.14 (95%CI 0.02-1.14), which did not reach conventional level of statistical significance (p = 0.066) due to small number of events. A third of MDS pts had high-risk disease per IPSS-R prognostic score (7/20 evaluable pts). 10 (of 11 NS MDS pts with available NGS data) pts had ≥1 nonsynonymous mutations and most pts (6/11) harbored multiple [Median (IQR): 2 (1-3)] high-risk mutations despite a younger median age of the cohort. Conclusions: In this large cohort of adults with obesity, we observed a lower incidence of MDS after IWL achieved with BSx. Higher prevalence of high-risk-MDS mutations in a relatively young NS-cohort with obesity warrants further investigation of effects of IWL on clonal evolution, its clinical relevance, and role of screening in halting progression of CH to MDS via early detection and targeted intervention. [Table: see text]
High frequency of germline mutations in DDR associated genes SLX4, MSH6, CDK4, TSC2, and BRCA2 might contribute to the occurrence of MPLC.
Authors: Weiquan Gu, Ning Zhao, Jun Ye, Fei Wang, Ye Xiao, Mingzhe Xiao
Journal: Journal of Clinical Oncology (2023)

e20514 Background: Multiple primary lung cancer (MPLC) is the presence of two or more distinct and separate lung tumors in a single patient. Each is considered a primary tumor rather than a metastasis from another site. This phenomenon has been the subject of several studies in recent years due to its increasing incidence and potential implications for patient management and prognosis. The underlying causes of MPLCs are not fully understood. Still, several factors have been proposed to contribute, including the genetic predisposition of carcinogens, such as those in the TP53, BRCA1, and BRCA2 genes, which are associated with an increased risk of developing MPLCs, as well as other cancers. Whether the presence of germline genetic mutations can increase an individual's susceptibility and contribute to the development of MPLCs is not clear yet. Here we reported the landscape of germline mutations of 77 MPLC patients. Methods: We retrospectively analyzed the somatic and germline mutations from 77 MPLC patients by NGS analysis. The GO and KEGG analyses were performed based on the top 30 most frequent germline mutations. Results: Among the 77 patients, 21 (27.27%) were male, and 56 (72.73%) were female. The median age was 60 (26-82) years old. The top 5 frequent germline mutated genes were SLX4 (34.92%), MSH6 (39.68%), CDK4 (26.98%), TSC2 (25.4%), and BRCA2 (25.4%). The top 5 frequent somatic mutated genes were EGFR (80.95%), CDK4 (26.98%), MCL1 (23.81%), SOCS1 (19.05%), and TP53 (19.05%). GO analysis of germline mutations revealed enrichment in ontologies such as response to radiation and UV, cell cycle regulation, a series of DNA damage repair associated ontologies, and telomere organization. KEGG analysis indicated that these germline mutations were enriched in the PI3K-Akt pathway, microRNAs in cancer, TP53 pathway, Fanconi anemia pathway, cellular senescence, and many other cancer-associated pathways. Conclusions: Germline alterations in many genes coding for proteins regulating DNA repair and DNA damage response (DDR) to DNA double-strand breaks (DDSB) have been recognized as pathogenic factors in hereditary cancer predisposition. In our analysis, the MPLC patients contained widespread germline mutations in SLX4, MSH6, CDK4, TSC2, and BRCA2, which were all associated with DNA damage repair. Besides, GO analysis and KEGG analysis also revealed enrichment in DDR-associated ontologies or pathways (e.g., TP53 pathway, Fanconi anemia pathway, cellular senescence pathways). To our knowledge, an underlying hallmark of cancers is their genomic instability, which is associated with a greater propensity to accumulate DNA damage. The widespread of germline mutations in DDR-associated genes, including SLX4, MSH6, CDK4, TSC2, and BRCA2, might contribute to the gene instability and promote the development of MPLC.
Representation of age, race and ethnicity in real-world evidence (RWE), randomized clinical trial (RCT), and Surveillance, Epidemiology, and End Results (SEER) cancer patient registry data in advanced renal cell carcinoma (aRCC).
Authors: Marné Garretson, Danielle Gentile, Madison Brown, Parisa Asgarisabet, Richard Scott Swain, Andrew J. Klink, Bruce A. Feinberg
Journal: Journal of Clinical Oncology (2023)

e18672 Background: Representation of key demographic characteristics in real-world settings and clinical trial environments is medically necessary to address evidentiary gaps and disparities in clinical outcomes among patients with advanced renal cell carcinoma (aRCC). We characterized age, race, and ethnicity in patients with aRCC in real-world evidence (RWE), corresponding randomized controlled trials (RCTs), and Surveillance, Epidemiology, and End Results (SEER) data during contemporaneous periods spanning 2017-2022. Methods: Demographic characteristics were assessed from one RWE chart review study, two RCTs (Checkmate 214 and Keynote 426), and a SEER cohort based on RCT/RWE eligibility criteria and compared across data sources using 2-sided chi-square or t-tests. Results: Age, race and ethnicity were collected for 4,821 patients (RWE: n = 635, 13.2%; RCT: Checkmate 214 n = 1,096 and Keynote 426 n = 861, 40.6% across both RCTs; SEER: n = 2,229, 46.2%). RCT participants were younger at metastatic diagnosis (60.9 vs 65.1 years) and at 1L therapy initiation (60.9 vs 65.7 years) compared to patients in RWE and SEER, respectively (both p &lt; 0.0001). Black patients accounted for 17.2% in RWE, 1.6% in RCT, and 4.8% in SEER data, and Asian patients accounted for 6.3% in RWE, 11.8% in RCT, and 6.0% in SEER data. Hispanic representation was significantly higher in RWE studies than RCT studies, (15.0% vs 3.4%), P&lt; .001. A significantly greater proportion of white patients was observed in RCTs than RWE (84.5% vs 71.7%) and greater representation of non-Hispanic white patients was observed in SEER vs RWE (67.5% vs 60.3%), P&lt; .001 (Table 1). Conclusions: This study describes existing disparities in representation of age, race, and ethnicity among patients with aRCC in research. RCTs had lower representation of older, Black, and Hispanic patients with aRCC compared to SEER and RWE studies. Despite limitations including sparse data available among Hispanics in RCTs, RWE studies can provide greater visibility to traditionally medically underrepresented patients with aRCC. [Table: see text]
SARS-CoV2 vaccination response in pediatric oncology patients.
Authors: Amber Marie D'Souza, Manu Gnanamony, Maria Thomas, Thu Hien Nguyen, Pedro Antonio de Alarcon
Journal: Journal of Clinical Oncology (2023)

e22023 Background: There remains limited knowledge about the immune response to SARS-COV2 vaccination in pediatric oncology patients, which is essential to provide appropriate counseling and risk adaptation in this vulnerable population. The goal of this study was to understand immunogenicity after vaccination in pediatric oncology patients and determine if certain clinical factors impacted response. Methods: After institutional review board approval, we consented patients in our clinic who had diagnosis of cancer, were 0-25 years old, and actively receiving therapy, including chemotherapy, immunotherapy, and targeted therapy. We excluded patients who were completely vaccinated prior to their cancer diagnosis. Blood samples were collected pre-vaccination, as well as 2, 6, and 8-12 weeks after vaccination. Healthy children who were fully vaccinated could also consent as controls, with samples collected up to 6 months from vaccination. Demographic data, history of COVID19 infection, and complete blood counts around time of vaccination were collected. To study immunogenicity, we measured neutralizing antibodies by enzyme-linked immunoassay (ELISA, GenScript) and interferon gamma (INFl) secretion, which measures T cell response to viral antigens, by enzyme-linked immunospot (ELISPOT, Mabtech). Results: 16 patients enrolled on study, for which 11 were evaluable along with 7 control patients. Seven patients had acute lymphoblastic leukemia, two had sarcomas, one had chronic myeloid leukemia, and one had Hodgkin lymphoma. Overall, the pediatric oncology patients had a worse immune response to vaccination compared to controls. Only one patient, who had COVID19 prior to vaccination, had similar responses to controls. Patients were divided into inadequate (n = 6) and adequate response (n = 5) based on semiquantitative analysis of immune response at 8-12 weeks post vaccination. Inadequate response was primarily seen in acute lymphoblastic leukemia patients (5 of 6 patients) and those receiving highly cytotoxic chemotherapy. Adequate response was seen in patients receiving oral therapy or chemoimmunotherapy. No patients received steroids around the time of vaccination. The inadequate response group had the lowest absolute lymphocyte counts (ALC), but ALC was variable in the adequate response group. Numbers were too small to note a difference based on age, gender, ethnicity, or type of vaccine. Conclusions: Pediatric oncology patients have a suboptimal immune response to SARS-COV2 vaccination. Malignancy type, therapy modality, and to a lesser extent, ALC at the time of vaccination, are all associated with worse immunogenicity. This study supports the need for additional doses and boosters to provide better protection against COVID19 in pediatric oncology patients.